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The proteasomal de-ubiquitinating enzyme POH1 promotes the double-strand DNA break response
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The proteasomal de-ubiquitinating enzyme POH1 promotes the double-strand DNA break response
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Journal Article
The proteasomal de-ubiquitinating enzyme POH1 promotes the double-strand DNA break response
2012
Overview
The regulation of Ubiquitin (Ub) conjugates generated by the complex network of proteins that promote the mammalian DNA double‐strand break (DSB) response is not fully understood. We show here that the Ub protease POH1/rpn11/PSMD14 resident in the 19S proteasome regulatory particle is required for processing poly‐Ub formed in the DSB response. Proteasome activity is required to restrict tudor domain‐dependent 53BP1 accumulation at sites of DNA damage. This occurs both through antagonism of RNF8/RNF168‐mediated lysine 63‐linked poly‐Ub and through the promotion of JMJD2A retention on chromatin. Consistent with this role POH1 acts in opposition to RNF8/RNF168 to modulate end‐joining DNA repair. Additionally, POH1 acts independently of 53BP1 in homologous recombination repair to promote RAD51 loading. Accordingly, POH1‐deficient cells are sensitive to DNA damaging agents. These data demonstrate that proteasomal POH1 is a key de‐ubiquitinating enzyme that regulates ubiquitin conjugates generated in response to damage and that several aspects of the DSB response are regulated by the proteasome.
The POH1/Rpn11 de‐ubiquitinase edits ubiquitin chain signals at DNA damage sites, thereby modulating recruitment of break repair factors such as 53BP1 and RAD51.
Publisher
John Wiley & Sons, Ltd,Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group
Subject
/ DNA
/ DNA-Binding Proteins - metabolism
/ DUB
/ EMBO13
/ EMBO31
/ Enzymes
/ Humans
/ Intracellular Signaling Peptides and Proteins - metabolism
/ Jumonji Domain-Containing Histone Demethylases - metabolism
/ Mammals
/ Proteasome Endopeptidase Complex - metabolism
/ Rad51 Recombinase - metabolism
/ Trans-Activators - metabolism
/ Tumor Suppressor p53-Binding Protein 1
